Application of prolonged microdialysis sampling in carboplatin-treated cancer patients

Purpose  To determine the dose-limiting toxicity (DLT) and activity of combination with docetaxel and S-1 on unresectable gastric cancer. Patients and methods  Docetaxel was administered intravenously on day 1 and S-1 was administered orally on days 1–14, every 3 weeks. Doses of each drug in phase I study were docetaxel 60–75 mg/m² and S-1 60–80 mg/m². A phase II study was conducted with the recommended dose (RD) based on phase I. Results  Sixty-five patients (median age 54 years) were enrolled. The DLTs were neutropenia with fever or stomatitis. The RD was docetaxel 75 mg/m² and S-1 60 mg/m². Two patients (aged 66 and 64 years) developed septic shock during the initial part of phase II study. A phase I study at lower dose (docetaxel 60 mg/m² and S-1 80 mg/m²) was conducted for patients older than 60 years, and this dose was determined as the RD for these patients. In the phase II study, frequent grade 3/4 toxicities were neutropenia (47%) and febrile neutropenia (26%). The overall response rate was 50% (95% CI, 35–66%) and median survival was 15.3 months (95% CI, 10.0–20.6 months). Conclusions  Combination with docetaxel and S-1 was active against advanced gastric cancer and gave manageable toxicities. Supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412_CR01_0704_0001).     

Phase I dose escalation study of docetaxel with a fixed dose of S-1 in combination chemotherapy for advanced gastric cancer

Background  The primary objectives of this study were to estimate the maximum-tolerated dose (MTD) of docetaxel in combination with a fixed dose of S-1 and to determine the recommended dose (RD). Patients and methods  Patients with histologically proven gastric carcinoma with metastatic or locally advanced inoperable disease were eligible. Patients received intravenous docetaxel starting at 40 mg/m² (dose level 1), and stepwise dose increases to 50, 60, and 70 mg/m² were planned for successive patient cohorts (dose levels 2, 3, and 4, respectively) over 1 h on day 1 and oral S-1 administered at a fixed dose of 40 mg/m² twice daily on days 1–14, both drugs every 21 days. Results  A total of 13 patients were enrolled into this trial. All three patients at dose level 3 developed dose-limiting toxicities (DLT), and this level was declared to be the MTD. Hence, level 2 (docetaxel 50 mg/m²) was declared to be the RD for the next study. As 9 of the 13 enrolled patients responded to treatment, the overall objective response rate was 69.2% (95% CI, 44.1–94.3%). The median time to progression was 8.38 months (range 1.44–8.51) and the overall survival duration was 9.9 months (range 0.62–11.57). The most common grade 3/4 toxicity of docetaxel plus S-1 was neutropenia, which was tolerable and manageable. Conclusion  This regimen showed encouraging activity and a manageable safety profile in advanced gastric carcinoma and could be used in further randomized studies.     

Phase II study of docetaxel and cisplatin combination chemotherapy in metastatic gastric cancer

Purpose: Docetaxel, as a single agent, has demonstrated activity in patients with advanced gastric cancer and cisplatin has shown lack of overlapping toxicities with docetaxel. Therefore, we conducted a phase II study to assess the efficacy and the toxicity of a combination regimen of docetaxel plus cisplatin in patients with advanced gastric cancer who have never been treated with palliative chemotherapy. Methods: Ninety-two patients with metastatic gastric cancer were enrolled from April 2000 to March 2004. Patients with histologically confirmed gastric adenocarcinoma, at least one bi-dimensionally measurable lesion, no prior palliative chemotherapy and at least 6 months from the end of adjuvant chemotherapy were eligible for study entry. Docetaxel 75 mg/m² and cisplatin 75 mg/m² were given on day 1. The cycle was repeated every 3 weeks. The objective response was evaluated after three cycles of chemotherapy. Toxicity was assessed according to the National Cancer Institute common toxicity criteria scale version 2.0. Results: In total, 401 cycles were administered, with a median of 5 cycles per patient (range 1–9 cycles). The median age was 56 years (range 31–76). Eighty-six patients were evaluable for treatment response. The objective response rate was 43.5% (95% CI, 33.4–53.6) with one complete response and 39 partial responses. Twenty patients (21.7%) had stable disease and 26 patients (28.3%) had a progression. The median time to progression was 7.0 months (95% CI, 5.0–9.0) and the median overall survival was 11.5 months (95% CI, 9.5–13.4). The chemotherapy was generally well tolerated and the most common grade 3–4 toxicities were neutropenia (17.4%), nausea/vomiting (13.0%) and diarrhea (7.6%). Conclusion: The combination chemotherapy of docetaxel with cisplatin in advanced gastric cancer was tolerable for most patients and showed a promising antitumor activity as a first-line therapy.Keon Woo Park and Jin Seok Ahn contributed equally to this work.     

Oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer: a multicenter phase II trial of the Southern Italy Cooperative Oncology Group

Purpose  This phase II trial assessed the tolerability and efficacy of a triplet of oxaliplatin, irinotecan, and fluorouracil/folinic acid in advanced gastric cancer. Methods  Patients with unresectable or metastatic gastric cancer, unexposed to palliative chemotherapy, received oxaliplatin 85 mg/m² iv and irinotecan 150 mg/m² iv on day 1, 6S-folinic acid 250 mg/m² iv and fluorouracil 750 mg/m² iv on day 2, every 2 weeks. Response rate (RR) was assessed after a minimum of four cycles, and treatment continued up to 12 cycles. Results  Sixty-three patients were treated, with a median of eight (range 1–12) cycles/patient. Two complete and 19 partial responses were registered (RR 33% [95% CI, 22–46%]). Median progression-free survival was 7.5 (95% CI, 5.6–9.4) months, and median overall survival was 12.1 (95% CI, 10.8–13.4) months. Most common grade ≥3 toxicities were neutropenia (59%), febrile neutropenia (7%), vomiting (20%), and diarrhoea (10%). All-grade neurotoxicity affected 33% of patients. Conclusions  Oxaliplatin, irinotecan, and fluorouracil/folinic acid administered every 2 weeks are safe and active in advanced gastric cancer. SICOG trial 0405, EudraCT number 2006-0066869-16.     

Dose-finding study of docetaxel, oxaliplatin, and S-1 for patients with advanced gastric cancer

Purpose  To determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy on metastatic gastric cancer. Patients and methods  Docetaxel and oxaliplatin were administered intravenously on day 1 and S-1 was administered orally on days 1–14 of every 21-day cycle. The doses of docetaxel/oxaliplatin/S-1 in the phase I study were level −1A, 52.5/80/60 mg/m²; level −1B, 52.5/80/80 mg/m²; level 1A, 52.5/105/80 mg/m²; level 1B, 52.5/130/80 mg/m²; level 2A, 60/105/80 mg/m²; level 2B, 60/130/80 mg/m²; level 3A, 67.5/105/80 mg/m²; level 3B, 67.5/130/80 mg/m²; level 4A, 75/105/80 mg/m²; level 4B, 75/130/80 mg/m². Results  Nine patients were enrolled. One of six patients at level 1A and two of three patients at level 1B developed dose-limiting toxicity (febrile neutropenia) during the initial two cycles. Therefore, the doses used at levels 1B and 1A were defined as the MTD and RD, respectively. All patients were evaluated for toxicity and response. Six partial responses were noted, and the overall response rate was 67%. Conclusion  The RD of the DOS regimen in patients with advanced gastric cancer was docetaxel 52.5 mg/m² and oxaliplatin 105 mg/m² on day 1 and S-1 80 mg/m² on days 1–14 of every 21-day cycle. A phase II study using the RD is currently underway.     

Phase I/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

Purpose  We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. Patients and methods  The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m²) was given orally on days 1–21 every 35-day cycle (rest on days 22–35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m², stepping up to 70 mg/m² in 10-mg/m² increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. Results  The MTD of paclitaxel was estimated to be 60 mg/m², because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m². In the phase II portion, 22 patients were evaluated with 50 mg/m² paclitaxel and 80 mg/m² S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2–75.6%). The median survival time was 283 days (95% CI, 218–508 days). The median number of treatment courses was 4 (range 1–10), indicating that this regimen could be given repeatedly. Conclusions  This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.     

Weekly Taxotere and cisplatin with continuous-infusion 5-fluoruracil for the treatment of advanced gastric and esophageal cancer: a prospective, observational, single-institution experience

Abstract  

The combination of Taxotere (docetaxel), cisplatin, and prolonged-infusion 5-fluorouracil (5-FU) has emerged as an active treatment for advanced gastric cancer. However, the regimen proposed by van Cutsem et al. (J Clin Oncol 24:4991–7, 2006) is associated with significant toxicity and therefore alternative schedules are needed. In the present study, patients with advanced gastric or esophageal cancer received Taxotere 35 mg/m² and cisplatin 25 mg/m² on day 1, followed by 5-FU 180 mg/m²/day as a 7-day prolonged infusion. Drugs were given weekly for 3 consecutive weeks followed by 1 week’s rest. Cycles were repeated every 4 weeks. Overall, a total of 110 cycles were administered to 27 patients (median age 63 years, range 40–78 years). The median number of cycles per patient was 4 (range 2–6). Nine partial responses were obtained, resulting in an overall response rate of 33% [95% confidence interval (CI) 16–51], a median time to progression of 6.4 months (95% CI 5.4–7.4), and a median overall survival of 10.7 months (95% CI 6.6–14.8). Toxicity was mild; grade III-IV neutropenia was the most frequently observed side effect, in 9 administered cycles (8%); neutropenia was complicated by fever in 2 cycles. Other grade III–IV toxicities observed in >5% of patients were anemia and mucositis.     

A phase II study of irinotecan and docetaxel combination chemotherapy for patients with previously treated metastatic or recurrent advanced gastric cancer

Purpose  Irinotecan (I) and docetaxel (D), each of which has a unique mechanism of action, were recently introduced in the treatment of patients with advanced gastric cancer (AGC). We have evaluated the efficacy and safety of the ID combination for AGC patients after failure of fluoropyrimidine- or platinum-based chemotherapy. Materials and methods  Patients with relapsed or progressive AGC after prior fluoropyrimidine- or platinum-based chemotherapy were treated with I (160 mg/m², 90 min) followed by D (65 mg/m², 1 h) every 3 weeks. Because of the unacceptable toxicity among the first ten patients, the doses were reduced for I (120 mg/m²) and D (50 mg/m²) every 3 weeks. Results  Forty-nine patients, of median age 53 years (range, 27–68 years), were treated with 170 cycles of chemotherapy (median, 2 cycles; range, 1–12 cycles). Three patients achieved complete response and seven achieved partial response, resulting in an overall response rate (ORR) of 20.4% [95% confidence interval (CI), 9.1–31.7%], with a median duration of 7.1 months (range: 2.1–69.1 months). ORR was 60% (95% CI, 29.6–90.3%) for the higher dose and 10.3% (95% CI, 0.7–19.8%) for the lower dose. Median time to progression for all patients was 2.7 months (95% CI, 1.7–3.8 months) and the median overall survival was 8.9 months (95% CI, 6.6–11.3 months). Grade 3/4 toxicities included neutropenia (90%), febrile neutropenia (50%), asthenia (40%), and diarrhea (10%) with the higher dose and neutropenia (71%), febrile neutropenia (11%), diarrhea (24%), and asthenia (24%) with the lower dose. There were two possible treatment-related deaths. Conclusion  The combination of irinotecan and docetaxel, once every three weeks shows anti-tumor activity but is not feasible as a second-line treatment for AGC patients after failure of fluoropyrimidine- or platinum-based chemotherapy due to the high rate of toxicities. S. J. Sym and H. M. Chang have contributed equally to this article.     

A multicenter phase II trial of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin’s lymphoma

Purpose  We investigated the efficacy and toxicity of the etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx), in which oxaliplatin (Ox) was substituted for cisplatin in the ESHAP [etoposide (E), methylprednisolone (S), high-dose cytarabine (HA), and cisplatin (P)] regimen, for patients with refractory/relapsed aggressive non-Hodgkin’s lymphoma (NHL). Materials and methods  The ESHAOx consisted of E (40 mg/m² on days 1–4), S (500 mg on days 1–5), HA (2 g/m² on day 5), and Ox (130 mg/m² on day 1) every 3 weeks to a maximum of six cycles. Responses were assessed every three cycles. Results  Twenty-seven patients were enrolled (19 with relapsed and 8 with refractory; 10 with an IPI score of 3–5). The overall response rate was 63% [95% confidence interval (95% CI) 45–81%], including eight complete remissions (CR) and one unconfirmed CR (33%). The median duration of response was 9.9 months (95% CI 5.7–14.2 months). After a median follow-up of 18.6 months, the median progression-free and overall survival was 5.3 months (95% CI 3.9–6.7 months) and 15.1 months (95% CI 9.4–20.9 months), respectively, with a 1-year survival rate of 61.5%. Most common grade 3/4 hematologic toxicities were neutropenia (56%) and thrombocytopenia (35%), whereas no patient experienced grade 3/4 renal or neurotoxicity. Conclusion  The efficacy and toxicity profiles suggested that the ESHAOx can be an alternative option for patients with refractory/relapsed aggressive NHL. S. J. Sym and D. H. Lee contributed equally to this study.     

A phase II study of gemcitabine in combination with oxaliplatin as first-line chemotherapy in patients with inoperable biliary tract cancer

Purpose   The aim of this study is to investigate the efficacy and safety of gemcitabine and oxaliplatin combination chemotherapy as first-line therapy in patients with inoperable biliary tract cancer (BTC). Methods   The treatment of this non-randomized phase II study consisted of gemcitabine 1,000 mg/m² intravenously (i.v.) on day 1 and oxaliplatin 85 mg/m² i.v. on day 2 every 2 weeks until disease progression, unaccep toxicity or patients’ refusal. Results   From Sept 2006 to Oct 2007, 40 patients were enrolled. In the ITT analysis, the objective response rate was 15.0% and the disease control rate was 52.5%. The median overall survival (95% CI) was 8.5 months (6.4–10.7) and the time to progression was 4.2 months (0.5–7.9). For the 305 cycles, observed grade 3/4 toxicity was uncommon. Conclusions  Gemcitabine and dose adjusted oxaliplatin combination chemotherapy had moderate anti-tumor activity and was well tolerated as a first-line treatment for patients with inoperable BTC.     

A phase II study of oxaliplatin in combination with doxorubicin as first-line systemic chemotherapy in patients with inoperable hepatocellular carcinoma

Purpose  We designed a phase II trial of the combination with oxaliplatin and doxorubicin for patients with unresectable HCC to evaluate the overall response rate (ORR) and the toxicity. Methods  Forty patients with inoperable, systemic chemotherapy naive HCC were enrolled. Finally, 32 patients received oxaliplatin (130 mg/m²) and doxorubicin (60 mg/m²) every 3 weeks. Results  Eighty-two treatment cycles were administered (median 2 cycles, range 1–6). There was no treatment-related mortality. The ORR was 15.6% (95% CI, 3.3–28.7) with five partial responses. The median overall survival and median overall progression free survival were 31 weeks (95% CI, 22–40 weeks) and 12 weeks (95% CI, 5-19 weeks). Nausea and peripheral neuropathy were most frequent non-hematologic toxicities (nausea, n = 15; peripheral neuropathy, n = 10). The most frequent grade 3–4 hematologic adverse event was neutropenia (14 of 82 cycles) including three cases of febrile neutropenia. Conclusions  The combination of oxaliplatin and doxorubicin showed modest activity and a tolerable toxicity profile in advanced HCC patients.     

A multicentre phase II study to evaluate sequential docetaxel followed by capecitabine treatment in anthracycline-pretreated HER-2-negative patients with metastatic breast cancer

Introduction  Treatment of HER-2-negative metastatic breast cancer (MBC) patients after anthracycline exposure is controversial. Docetaxel/capecitabine is a promising regimen, but the administration schedule is not well established. Materials and methods  Treatment included 3 cycles of docetaxel 100 mg/m² day 1 every 21 days followed by 3 cycles of capecitabine 1250 mg/m²/12 h days 1–14. Patients not progressing were maintained with capecitabine 900 mg/m²/12 h on days 1–14 every 21 days until progression or unacceptable toxicity. Results  Fifty-three anthracycline-pretreated patients were enrolled: median age 54 years, ECOG grade 0–1 86.7%. Most of the women received adjuvant chemotherapy (81%) and 5 patients (9%) had had prior metastatic chemotherapy treatment. Median time from anthracycline exposure was 29 months. ORR (intent-to-treatment analysis) after the sequential therapy was 51% (CI 95% 37–65) with 15% (CI 95% 7–28) of patients reaching complete responses. Median time to progression was 8.2 (CI 95% 7.1–10.7) months, with 61.9% (CI 95% 45.6–76.4) of the patients free of disease after 6 months. Median overall survival was not reached after a median follow-up of 10.4 months, and 75% of the patients were alive after 14.3 months. Survival rate after 12 months was 81.1% (CI 95% 68.0–90.6). The most frequent NCI grade 3–4 toxicities were hair loss (28.3%), asthenia (15.1%), stomatitis (11.32%) and nausea (11.32%). Severe hand-foot syndrome rate was 7.5%. Conclusions  Sequential docetaxel-capecitabine is feasible, effective and well tolerated in first-line MBC treatment. Evaluation of this schedule in randomised studies is warranted.     

Gemcitabine plus docetaxel as first-line chemotherapy in patients with advanced non-small cell lung cancer: a lung cancer Galician group phase II study

Background Numerous phase II and III clinical trials have demonstrated a higher activity of combined gemcitabine plus docetaxel schedules against non-small cell lung cancer (NSCLC) than that of both agents in monotherapy. Methods This phase II study evaluated a 3-week based schedule of docetaxel 85 mg/m² (1-h i.v. infusion, d8) combined with gemcitabine 1,000 mg/m² (30-min i.v. infusion; d1,8) as first-line chemotherapy for patients with advanced NSCLC. Results Forty-one patients with non-resectable, stage IIIB/IV, and bidimensionally measurable disease were enrolled. A total of 182 chemotherapy cycles (median 6, range 1–6) was administered to 40 patients during the study; one patient did not receive chemotherapy due to a protocol deviation. Two patients were not evaluable for treatment efficacy. The overall response rate found was 44% (95% CI, 29–59%): three patients (7%) had a complete response and 15 patients (37%) had a partial response (median duration of response = 4.0 months). With a median follow-up of 8.7 months, the median time to disease progression was 4.4 months and the median overall survival was 7.3 months. The combined gemcitabine plus docetaxel chemotherapy was well tolerated except for pulmonary toxicity. The main grade 3–4 hematological toxicity was neutropenia (28% of patients, 9% of cycles). Two cases of febrile neutropenia were reported. The main grade 3–4 non-hematological toxicity was pulmonary toxicity (23% of patients, 6% of cycles). Conclusion Gemcitabine 1,000 mg/m² on days 1 and 8 in combination with docetaxel 85 mg/m² on day 8 given in 3-week cycles is an active and well-tolerated first-line chemotherapeutic regimen for advanced NSCLC.     

A multiple-center phase II study of biweekly oxaliplatin and tegafur–uracil/leucovorin for chemonaive patients with advanced gastric cancer

Purpose  The current study assessed the efficacy and safety of biweekly oxaliplatin combining oral tegafur–uracil/leucovorin in treating chemonaive patients with advanced gastric cancer. Methods  Eligible patients were 18–75 years old, had stage IV disease or post-surgery recurrence, no prior palliative chemotherapy, and an ECOG performance status of 0–2. Patients in the current study received 2-h i.v. infusion of oxaliplatin at a dose of 100 mg/m² after diluting in 500 mL 5% dextrose/water (dexan premedication), and 5-HT3 antagonist biweekly. Oral tegafur–uracil and leucovorin was given at a dose of 300 mg/m²/day and 60 mg/day three times daily from day 1 to 21, respectively, followed by a 1-week rest. Response assessment was based on the RECIST criteria and was performed every two courses. Toxicity was assessed according to NCI common toxicity criteria version 2. Results  From October 2003 to April 2006, 57 patients were evaluated (55 eligible) with a median age of 61 years (range 31–75). According to the assessment of response in 48 evaluable patients, partial response rate was 24/48 (50.0%) (95% CI: 35.23–64.73%) and stable disease was observed in 11 patients (22.92%), and diseased progressed in 13 patients (27.08%). Mean number of oxaliplatin cycles was 3 (0.5–6.5). Median time to progression was 177 days. Median overall survival was 318 days. Major-grade (III/IV) toxicities were diarrhea 25.5%, vomiting 16.5%, anemia 10.9%, numbness 12.7%, thrombocytopenia 7.3%, neutropenia 3.6% and leucopenia 1.8%. Conclusions  Biweekly, oxaliplatin combining oral tegafur–uracil/leucovorin in treating patients with advanced gastric cancer showed acceptable activity and manageable toxicity. This study was presented in part at the 7th International Conference of the Asian Clinical Oncology Society, September 14–28, 2006, Beijing, China.     

Simplified FOLFIRI in pre-treated patients with metastatic gastric cancer

Purpose  Second-line chemotherapy in patients with metastatic gastric cancer (MGC) pre-treated with cisplatin is not a standard option. We studied a combination of irinotecan, fluorouracil and folates. Methods  Patients progressive to cisplatin-based chemotherapy were enrolled. Irinotecan 180 mg/m², folinic acid 200 mg/m², and fluorouracil 400 mg/m² were given on day 1, immediately followed by fluorouracil 2,400 mg/m² 46 h continuous infusion (simplified FOLFIRI), every 2 weeks. Results  Between June 2002 and May 2003, 28 patients were treated. Median age was 57 years (range 38–68). Most patients had a distal primary (90%), and metastatic disease (71%). Partial response was obtained in six patients (21%, 95% CI 8–41) and stable disease in eight (21%, 95% CI 13–41). Among the six responsive patients three were refractory to docetaxel. At a median follow-up of 2.9 years median time to progression was 4 months (95% CI: 2–5), and median overall survival was 5 months (95% CI 4–9). Toxicity was mild, without treatment-related deaths or life-treating adverse events. Conclusions  Simplified FOLFIRI was moderately active and well tolerated in unselected patients with MGC pre-treated with cisplatin-based chemotherapy. Its role in patients refractory to taxanes is promising and warrants further investigation.     

Systemic exposure of oxaliplatin and docetaxel in gastric cancer patients with peritonitis carcinomatosis treated with intraperitoneal hyperthermic chemotherapy

In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m² hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m²). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5110⁻³ mg/ml for oxaliplatin, 89110⁻⁶ mg/ml for docetaxel (dose 50 mg/m²) and 113110⁻⁶ mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.     

A phase II study of bevacizumab,oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers

Background: Bevacizumab has demonstrated antitumor activity in multiple diseases. This phase II study was undertaken to determine the effects of adding bevacizumab to a regimen of docetaxel and oxaliplatin in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction.Patients and methods: Previously untreated patients with locally advanced or metastatic disease and a performance status (PS) of 0–1 were eligible for this study. Patients received bevacizumab at 7.5 mg/kg, docetaxel at 70 mg/m², and oxaliplatin at 75 mg/m² administered on day 1 of a 21-day cycle. The primary end point of the study was progression-free survival (PFS).Results: A total of 38 eligible patients (median age 57 years, 45% gastric, 55% PS 0) were enrolled on to the study. Median PFS was 6.6 months [95% confidence interval (CI) 4.4–10.5] and median survival 11.1 months (95% CI 8.2–15.3). Complete responses were documented in 2 (5%) patients, partial responses in 14 (37%), and stable disease in 14 (37%). No treatment-related deaths were observed. The most commonly reported grade 3–4 toxicity was neutropenia (34%), and gastrointestinal perforation occurred in three patients (8%).Conclusion: The combination of bevacizumab, docetaxel, and oxaliplatin has promising activity for further evaluation in randomized trials.     

Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer

Purpose  The aim of this study was to evaluate the activity and safety of oxaliplatin/5-fluorouracil-based chemo-radiotherapy in patients with not radically resectable locally advanced esophageal cancer. Methods  Fifty-nine patients with adeno or squamous-cell carcinoma received oxaliplatin (60 mg/m²), and leucovorin (20 mg/m² on days 1,8,15,29,36,43,50,57) followed by continuous infusion fluorouracil (200 mg/m² per day on days 1–22 and 29–64) with radiotherapy (1.8 Gy daily fractions to a total dose of 45 Gy, from days 29 to 64). When feasible, surgery was scheduled 6–8 weeks after chemo-radiotherapy completion. The primary endpoint was 1-year progression-free survival. Results  Forty (68%) patients completed treatment without modifications. An objective clinical response was seen in 35 patients (59%). Esophagectomy was possible in 33 patients and a complete resection (R0) was achieved in 26 (79%) with 6 pathologic complete responses (pCR) and 3 near pCR. At a median follow-up of 39.7 months for the surviving patients, the median progression-free and overall survivals were 11 months (95% CI 6.5–14) and 18.5 months (95% CI 13–29). The 1-year progression-free and overall survivals were 47.5% (95% CI 34–59.5%) and 63% (95% CI 49–74%). Major toxicities were esophagitis (20% G3 and 5% G4) and diarrhea (8.5% G3 and 8.5% G4). Hematological toxicity (7% G3 and 3% G4) was less common; severe neurotoxicity (3% G3) was infrequent. Conclusions  Concurrent oxaliplatin, leucovorin, fluorouracil and radiotherapy followed or not by esophagectomy has a tolerable toxicity and promising activity in locally advanced esophageal cancer. Presented in part at the 41st annual meeting of the American Society of Clinical Oncology, Orlando, FL, USA, May 13–17, 2005, the 107th Annual Meeting of the Italian Surgery Society, Cagliari, Italy, October 9–12, 2005 and the 17th ICACT Meeting, Paris, France, January 30–February 2, 2006.     

A phase II study of docetaxel as salvage chemotherapy in advanced gastric cancer after failure of fluoropyrimidine and platinum combination chemotherapy

Purpose Fluoropyrimidine (F) and platinum (P) combination chemotherapy has been widely used as a first-line treatment of advanced gastric cancer (AGC). Docetaxel has shown promising activity against this disease. In this study, we explored the efficacy and safety of docetaxel monotherapy as salvage chemotherapy in AGC after F and P combination chemotherapy failed. Materials and methods From October 2004 to October 2005, 49 eligible patients were enrolled in this study. The median treatment-free interval was 28.0 days, and 81.6% of patients had suffered cancer progression within 4 months after the withdrawal of first-line chemotherapy. Docetaxel was given IV at a dose of 75 mg/m² every 3 weeks, together with dexamethasone prophylaxis. Results A total of 182 cycles of docetaxel were administered with a median of 3 (range 1–9) cycles. From an intention-to-treat analysis, eight patients achieved objective response with a response rate of 16.3% (95% CI, 6.0–26.6). The median response duration was 4.7 months. A total of 20 patients showed stable disease, but 17 patients suffered disease progression. At a median follow-up duration of 11.3 months for surviving patients (range 6.3–18.8 months), the median time to disease progression was 2.5 months (95% CI, 2.3–2.7) and the median overall survival time since the start of docetaxel monotherapy was 8.3 months (95% CI, 6.7–9.8). Grade 3/4 neutropenia and febrile neutropenia occurred in 18.4% of patients and in 5.4% of cycles. The incidence of non-hematologic toxicities of grade 3 or worse was asthenia 32.7%, diarrhea 10.2% and peripheral sensory neuropathy 8.2%. Conclusion Docetaxel at 75 mg/m² is active against AGC as second-line chemotherapy after prior exposure to F and P combination chemotherapy. The toxicity profile is moderate.     

Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma

Purpose  To determine the efficacy and safety of the combination of gemcitabine plus oxaliplatin, with and without rituximab, in patients with relapsed/refractory B-cell lymphoma unsuitable for high dose therapy. Methods  Patients were prospectively enrolled in two subsequent trials, GEMOX [gemcitabine (1200 mg/m², days 1 and 8) and oxaliplatin (120 mg/m², day 2), three-weekly] and R-GEMOX [rituximab (375 mg/m², day 1), gemcitabine (1200 mg/m², day 1) and oxaliplatin (120 mg/m², day 2), bi-weekly], up to six courses. Results  Sixty-two patients were enrolled: GEMOX [n = 30; median age, 66 years (range, 46–85); previous chemotherapy ≥2, 70%; PS ECOG ≥ 2, 57%]; R-GEMOX [n = 32; median age, 65 years (range 32–79); previous chemotherapy ≥2, 75%; PS ECOG ≥ 2, 47%]. Overall and complete response rates were 57 and 30% (95% CI, 15–49) for GEMOX and 78 and 50% (95% CI, 32–68) in R-GEMOX, respectively. Grade 3/4 neutropenia occurred in 57 and 47% of cycles and grade 3/4 thrombocytopenia in 26 and 17% of courses for GEMOX and R-GEMOX, respectively. At 42 months, the failure-free survival (FFS) was 7% (95% CI, 0–16) for GEMOX and 28% (95% CI, 9–47) for R-GEMOX (P = 0.014), with overall survivals of 7 (95% CI, 0–16) and 37% (95% CI, 20–55), respectively (P = 0.016). Conclusions  Both regimes showed good tolerability and appealing response rates. FFS was more prolonged in R-GEMOX, but patients continuously relapsed without a clear plateau on survival curves.